1. Field of the Invention
The invention is generally related to aerosol formulations delivered by metered dose inhalers (MDIs). More particularly, the invention is directed to aerosol formulations which include vasoconstricting agents and the local anesthetic agent lidocaine in its base form dissolved in hydrofluorocarbon propellants.
2. Description of the Prior Art
Vasoconstriction of blood vessels is achieved by stimulation of the alpha receptors in the smooth muscle cells of the blood vessel wall. Vasoconstriction is desirable in some clinical situations both systemically to correct hypotension and locally to reduce regional blood flow. The alpha-1 adrenergic recepters, found in the smooth muscle cells of the peripheral vaculature of the coronary arteries, skin, uterus, intestinal mucosa and splanchnic beds, mediate vasoconstriction. These receptors serve as postsynaptic activators of vascular and intestinal smooth muscles as well as endocrine glands. Their activation results in either decreased or increased tone, depending upon the effector organ. The response in resistance and capacitance blood vessels is constriction. Alpha-1 adrenergic agonists include the natural catecholamines, epinephrine, norepinephrine and dopamine, and the synthetic noncatecholamines such as ephedrine, mephentermine, amphetamines, metaraminol, phenylephrine and methoxamine.
Phenylepherine is considered a potent pure alpha-1 agonist drug which increases venous as well as arterial constriction. Phenylephrine is used intravenously in small doses of approximately 1 .mu.g/kg body weight to cause systemic vasoconstriction and elevation of blood pressure. It is also used regionally to cause vasoconstriction when injected with local anesthetic agents to provide prolonged nerve conduction block.
Phenylephrine has been found to provide excellent decongestion of the nasal mucosa by exerting its alpha-1 mediated vasoconstricting effect on the mucosal blood vessels. This directly opposes the histamine-mediated vasodilation and reduces mucosal oedema and vascularity. Other agents that have been used for this effect are ephedrine and cocaine.
Cocaine possesses both anesthetic and vasoconstricting properties. These properties make it suitable to provide both topical anesthesia and vasoconstriction of the nasal mucosa to improve patient tolerance of nasal catheterization during nasotracheal intubation, nasogastric tube insertion, or fiberoptic examination of the nose. Vasoconstriction results in shrinking of the nasal mucosa with enlargement of the nasal passage and reduced bleeding during nasal procedures.
Although cocaine provides good vasoconstriction and is well tolerated by most patients, there are significant problems with its use. One such problem is that even small doses (approximately 30 mg for example) may cause systemic toxicity. Another problem relates to the potential diversion and illicit use of cocaine by medical personnel. The handling and storage of controlled substances involves additional administrative costs and risks.
Lidocaine is similar to cocaine in effectiveness as a local anesthetic, but it does not vasoconstrict the mucosa and thus dilate the nasal passage. For this reason, phenylephrine has been combined with lidocaine to reduce nasal congestion. The combination of lidocaine and phenylephrine has been advocated as an alternative to cocaine and its efficacy evaluated in a number of studies.
Currently, lidocaine and phenylephrine are required to be mixed by the clinician before applying the solution. Suitable recommended combinations are 3-4% lidocaine hydrochloride in water mixed with 0.25-1% phenylephrine hydrochloride, also in water. The aqueous solution is then delivered to nasal mucosa as a spray using a conventional manual atomizer or a multi-orificed cannula and syringe delivery system. The optimum dose used with this spray application is 1.25-1.5 mg phenylephrine hydrochloride and 12-15 mg lidocaine hydrochloride per nostril of adult patients.
The methods of delivery and efficacy of lidocaine and phenylephrine are discussed and evaluated in the following studies: Curtis N. Sessler et al., Anesthesiology 64:274-277 (1986); Jeffrey Gross et al., Anesthesia & Analgesia 63:915-918 (1984); and Robert M. Middleton et al., Chest 99:5:1093-1096 (1991).
Drug deposition in the nasal cavity is reviewed in Volume 39 of the "Drugs and the Pharmaceutical Sciences" series titled Nasal Systemic Drug Delivery, edited by Yie W. Chien, Kenneth S. E. Su and Shyi-Feu Cheng and published by Marcel Dekker, Inc. in 1989.
"The deposition of aerosols in the respiratory tract is a function of particle size and respiratory patterns. The density, shape and hygroscopicity of the particles and the pathological conditions in the nasal passage will influence the deposition of particles, whereas the particle size distribution will determine the site of deposition and affect the subsequent biological response in experimental animals and man."
"A uniform distribution of particles throughout the nasal mucosa could be achieved by delivering the particles from a nasal spray using a pressurized gas propellant."
Factors related to the dosage form of the drug found to affect the pharmacokinetics of nasal absorption include concentration of active drug, physiological properties of active drug, density/viscosity properties of the formulation, pH/toxicity of dosage form, and pharmaceutical excipients used.
Highly concentrated drugs which are lipid soluble at nasal pH of 5.5 to 6.6 and, when dissolved in a minimal amount of excipient, will be rapidly and extensively absorbed.
Lidocaine base is freely lipid soluble and will cross mucous membranes readily. It is insoluble in water and thus not suitable for use in an aqueous suspension, requiring ethanol or the like to obtain a liquid solution. Some way to produce a fine spray of lidocaine base would be advantageous for delivery to the nose.
Vasoconstricting agents such as phenylephrine are usually used in their salt forms which are water soluble and thus suitable for intravenous injection.
MDIs have been used extensively and have proven to be an effective means of producing a reproducible preselected dose of medicament in a predictable spray pattern and droplet size. This is particularly advantageous when delivering potent drugs where the need for reliable drug delivery is important and where overdoseage leads to dangerous clinical side-effects.
A problem with the use of MDIs relates to the chlorofluorocarbon (CFC) propellants which have been used in MDIs. All chlorine-containing halohydrocarbons have been implicated in the destruction of the earth's ozone layer with subsequent adverse effects on human and animal life. World-wide treaties have called for a ban on these propellants due to their alleged impact on the earth's ozone layer. The most widely recognized CFC alternatives are hydrofluorocarbon (HFC) propellants, such as 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane, and these propellants have been readily adopted in the refrigeration, polymer foam blowing, and electronic cleaning industries. However, HFC propellants have been found to behave differently than CFC propellants in the MDI environment. In particular, it has been found to be very difficult to solubilize or disperse pharmaceuticals in HFCs. Without solubilization or uniform dispersability in the propellant, the MDI cannot provide a reproducible and efficacious dose of medicament. Much work has been performed in the area of designing new surfactants and identifying co-solvents that can be used to solubilize or disperse pharmaceuticals in HFC propellants.
To date, no MDI pharmaceutical products that utilize HFC propellants have been approved for use by any industrialized country. Although, reports on recent submissions to regulatory agencies suggest that 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoroethane based MDIs are the most likely CFC-alternative MDIs to gain approval in the near future.
The object of aerosolized medication delivery by MDI is to provide the medicament in stable suspension or solution form in the propellant in a suitable concentration for clinical effect, with minimal or no additives. The droplet size is predictable and is a function of the suspended particle size in a suspension formulation or the relative volume of drug and its cosolvents to the propellant volume in a solution formulation. The propellant should constitute at least about 45% of the total formulation weight and preferably about 60-98% of the formulation weight.
Lidocaine and phenylephrine have been shown to exert independent effects on the nasal mucosa that result in vasoconstriction and topical anesthesia. Both of these effects have been found to be helpful during procedures involving manipulation or examination of the nose. The clinical effect is similar and considered superior in efficacy to cocaine, but the need to premix the solution and also to provide a suitable way to deliver a solution or suspension thereof has prevented their combined use from gaining universal acceptance as well as from being employed for all nasal manipulations such as nasogastric tube insertion, where its use should be advantageous to the patient.
Other clinical situations where a combined lidocaine/vasoconstricting agent formulation, such as lidocaine/phenylephrine, would be in providing topical anesthesia and vasoconstricting in the upper airway, open skin wounds, the urethra, anus, and the cervix and vagina.
The present invention provides a solution to this long-standing shortcoming or deficiency of the art.